Pancreatic cancer ranks as the fourth leading cause of cancer mortality in the US. It has the worst prognosis of all cancers, with a 5-year survival rate of <3%. Pancreatic cancer is often detected too late for surgery to be helpful and is highly resistant to current chemotherapy and radiation treatment. Currently, the only curative treatment for pancreatic cancer is surgery, but only 15% of patients are candidates for surgery at the time of presentation, and only 20% patients who undergo a curative operation are alive after 5 years. Therefore, new options for prevention and treatment are needed. This proposal is based on the use of green tea polyphenol, epigallocatechin-3-gallate (EGCG), which exerts significant inhibitory effects on diverse cellular events associated with tumor initiation, promotion and progression. Besides these advances, the intracellular mechanisms by which EGCG inhibits proliferation and induces apoptosis in pancreatic cancer cells are not well understood. Since EGCG is non-toxic, its worldwide interest as a cancer preventive agent has increased. Rationale for preclinical evaluation of EGCG against pancreatic cancer comes from our preliminary studies, which led us to hypothesize that EGCG will inhibit ras-dependent PI3K/Akt and MAP kinase activities, and these two pathways will converge to regulate FOXO transcription factors, cell growth and apoptosis in pancreatic cancer cells. EGCG will be highly effective in suppressing growth of human pancreatic cancer cells due to its ability to induce cell cycle arrest and apoptosis through regulation of FOXO transcription factors. The specific aims of the project are: (1) To examine the molecular mechanisms by which EGCG induces cell cycle arrest and apoptosis in pancreatic cancer cells, (2) To determine the effects of oral administration of EGCG on growth and regression of human pancreatic cancer cells implanted in nude mice, and (3) To determine in vivo efficacy of EGCG administration on pancreatic carcinogenesis using KrasG12D transgenic mouse model. This transgenic mouse model faithfully reproduces the histological features of human pancreatic cancer. Since EGCG is non-toxic, its worldwide interest as a cancer preventive agent has increased. Rationale for preclinical evaluation of EGCG against pancreatic cancer comes from our preliminary studies, which led us to hypothesize that EGCG will inhibit ras-dependent PI3K/Akt and MAP kinase activities, and these two pathways will converge to regulate FOXO transcription factors, cell growth and apoptosis in pancreatic cancer cells. EGCG will be highly effective in suppressing growth of human pancreatic cancer cells due to its ability to induce cell cycle arrest and apoptosis through regulation of FOXO transcription factors. The specific aims of the project are: (1) To examine the molecular mechanisms by which EGCG induces cell cycle arrest and apoptosis in pancreatic cancer cells, (2) To determine the effects of oral administration of EGCG on growth and regression of human pancreatic cancer cells implanted in nude mice, and (3) To determine in vivo efficacy of EGCG administration on pancreatic carcinogenesis using KrasG12D transgenic mouse model. This transgenic mouse model faithfully reproduces the histological features of human pancreatic cancer. Studies outlined in this proposal are highly significant because they will validate Kras transgenic mouse model for pancreatic cancer prevention and establish a clinical potential of EGCG that can delay the onset and/or progression of human pancreatic cancer.